NNT is a key regulator of adrenal redox homeostasis and steroidogenesis in male mice
Author(s)
Type
Journal Article
Abstract
Nicotinamide nucleotide transhydrogenase, NNT, is a ubiquitous protein of the inner mitochondrial membrane with a key role in mitochondrial redox balance. NNT produces high concentrations of NADPH for detoxification of reactive oxygen species by glutathione and thioredoxin pathways. In humans, NNT dysfunction leads to an adrenal-specific disorder, glucocorticoid deficiency. Certain substrains of C57BL/6 mice contain a spontaneously occurring inactivating Nnt mutation and display glucocorticoid deficiency along with glucose intolerance and reduced insulin secretion. To understand the underlying mechanism(s) behind the glucocorticoid deficiency, we performed comprehensive RNA-seq on adrenals from wild-type (C57BL/6N), mutant (C57BL/6J) and BAC transgenic mice overexpressing Nnt (C57BL/6JBAC). The following results were obtained. Our data suggest that Nnt deletion (or overexpression) reduces adrenal steroidogenic output by decreasing the expression of crucial, mitochondrial antioxidant (Prdx3 and Txnrd2) and steroidogenic (Cyp11a1) enzymes. Pathway analysis also revealed upregulation of heat shock protein machinery and haemoglobins possibly in response to the oxidative stress initiated by NNT ablation. In conclusion, using transcriptomic profiling in adrenals from three mouse models, we showed that disturbances in adrenal redox homeostasis are mediated not only by under expression of NNT but also by its overexpression. Further, we demonstrated that both under expression or overexpression of NNT reduced corticosterone output implying a central role for it in the control of steroidogenesis. This is likely due to a reduction in the expression of a key steroidogenic enzyme, Cyp11a1, which mirrored the reduction in corticosterone output.
Date Issued
2018-01-01
Date Acceptance
2017-10-18
Citation
Journal of Endocrinology, 2018, 236 (1), pp.13-28
ISSN
0022-0795
Publisher
BioScientifica
Start Page
13
End Page
28
Journal / Book Title
Journal of Endocrinology
Volume
236
Issue
1
Copyright Statement
© 2018 The authors This work is licensed under a Creative Commons Attribution 3.0 Unported License.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/29046340
PII: JOE-16-0638
Subjects
C57BL/6J MICE
CELLS
Endocrinology & Metabolism
FAMILIAL GLUCOCORTICOID DEFICIENCY
HEMOGLOBIN
Life Sciences & Biomedicine
MITOCHONDRIA
MUTATION
nicotinamide nucleotide transhydrogenase
NICOTINAMIDE NUCLEOTIDE TRANSHYDROGENASE
OXIDATIVE STRESS
PROTEIN
redox homeostasis
REDUCTIVE STRESS
RNA sequencing
ROS scavengers
Science & Technology
steroidogenesis
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2017-10-18